Resistance of Streptococcus Pneumoniae to Macrolides in Iran.

Background: Antimicrobial resistance of Streptococcus pneumoniae (S. pneumoniae) has shown major changes in recent years. On the other hand, macrolide antibiotics are being increasingly used in clinical practice. Several studies have reported increased resistance to this group of antibiotics, while there is no comprehensive information in this area. Accordingly, the present study was designed to estimate the resistance of S. pneumoniae to macrolides in Iran. Materials and Methods: In this review, articles (2000–2017), evaluating the level and type of S. pneumoniae resistance to macrolides in Iran, were extracted by searching different databases, and the results were analyzed. Results: A total of 25 relevant articles were retrieved and analyzed. Overall, 2723 cases had been recruited in these studies. The mean percentage of resistance to macrolides was estimated at 48.43% (CI, 38.8–57.9%). In the majority of reported cases, the resistance mechanisms included ribosomal methylation (i.e., ermB mutation), dual resistance, and efflux-mediated resistance. Conclusion: Based on the findings, the resistance rates are considerable in different cities of Iran. Therefore, without determining the type of drug resistance in clinical samples, use of macrolides is not recommended for treatment purposes. In addition, considering the type of resistance mechanisms in Iran, use of higher drug doses is probably ineffective.


TANAFFOS
Macrolides are a class of antibiotics, which have been used for many years as a treatment for pneumococcal infections. These drugs reversibly bind to 50S ribosomal subunit and inhibit RNA-dependent synthesis of proteins.
The widespread use of this class of drugs has led to a gradual increase in resistance rates. The resistance mechanisms against these agents are diverse and include ribosomal target site alteration, alteration in antibiotic transport, and antibiotic modifications (1). Each of these mechanisms has a different genetic basis.
Two main mechanisms, i.e., efflux-mediated drug resistance and ribosomal target site alteration, are encoded by mef(A) and erm(B) genes, respectively; resistance may also occur due to a combination of these mechanisms (4). It seems that each of these mechanisms causes a different level of resistance. Changes in the erm gene, which modify 23S ribosomal RNA, cause high levels of resistance, while the efflux-mediated mechanism leads to medium to low levels of resistance (> 64 g/mlM1C). Overall, according to previous studies, the relative distribution of these 2 mechanisms varies greatly in different parts of the world.
Since the selection of treatment strategies depends on the involved resistance mechanism, further information seems necessary for determining the type of resistance in clinical practice. The highest prevalence of macrolide resistance has been reported in the Far East (Taiwan, 98%; South Korea, 88%; Japan, 78%). Based on previous studies, the prevalence rates vary among countries in the same continent or even neighboring countries. For instance, in Greece and Turkey, as neighboring countries, the prevalence rates have been estimated at 29 and 2%, respectively (5). In addition, according to different studies, the prevalence of resistance varies greatly in Western Europe, ranging from 48-58% in France to 17% in Germany and 9% in England (5).
It seems that resistance to macrolides is associated with the use of these antibiotics in each region. For instance, low resistance rates have been reported in Northern European countries, whereas the prevalence of resistance is quite high in Southern and Eastern Europe (6). In addition to
All articles written in English or Farsi (published since 2000) were retrieved. Studies, which did not address S. pneumoniae resistance to macrolides, were excluded from the analysis. On the other hand, articles with other objectives, which provided information on macrolide resistance, were examined. Studies including less than 10 cases were excluded from the analysis. In addition to articles retrieved with this method, the reference lists were reviewed, as well. Overall, studies which contained relevant and unrepetitive information were included in the final analysis.
The required information, including microbial resistance pattern, method of resistance identification, study population, duration, type of clinical specimens, type of study sample (patients or healthy people), and location of the study, was extracted and studied independently.

RESULTS
According to the research method, 25 articles were considered relevant and eligible after detailed examination.
In total, 2723 cases had been analyzed in these studies (minimum, 12; maximum, 573). The mean number of cases in the retrieved articles was 116.7±108.9. In total, 8 studies included children, 2 were performed on adults, and 4 were carried out on both age groups (unidentified in 5 articles).
The majority of studies (14 articles) were conducted in Tehran, followed by Zahedan (3 articles), Shiraz (2 articles), Birjand, Hamadan, Kashan, Kermanshah, Shahrekord, and Yazd. The results are presented in Table 1. In contrast, erm(A) gene has not been reported in any previous study (10,12,13,17). According to the literature, Previous studies have also shown that macrolide resistance is completely dependent on the geographical region, with rates ranging from nearly 10 to 100% (1

CONCLUSION
In general, macrolides are not suitable options for clinical use against S. pneumoniae, given their widespread use in Iran (available to patients without prescription) and high resistance of pneumococci to these antibiotics.
Therefore, use of macrolides in clinical settings, without knowledge of resistance patterns, can be risky. In addition, considering the type of resistance to macrolides (dominance of methylation mechanism or dual resistance), use of higher drug doses is not a suitable method for preventing efflux-mediated resistance in Iran. In addition, monitoring of antibiotic use and prescription should be reviewed and revised, and more serious and practical measures need to be adopted.